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Limited data exist on the pharmacokinetic profile of novel direct acting antivirals in kidney transplant recipients. Daclatasvir is primarily eliminated via the biliary route and sofosbuvir via the renal route; here we report the pharmacokinetic profile of combined treatment with these compounds in a prospective study of hepatitis C virus positive kidney transplant recipients (EudraCT: 2014-004551-32). In this study plasma samples of 16 HCV positive kidney transplant recipients receiving daclatasvir and sofosbuvir were collected at 4 time points at day 1, 7, 14, 21, 56, and 84 after start of treatment. Inclusion criteria were stable graft function and an estimated GFR (eGFR) > 30mL/min/1.73m. Daclatasvir, sofosbuvir and GS-331007 (inactive metabolite of sofosbuvir) plasma concentrations were determined using ultra-performance liquid chromatography quadrupole time of flight mass spectrometry. All patients showed a rapid virological response with HCV RNA below the detection limit 21 days after the start of therapy (medium time to viral clearance). No difference of the areas under the concentration-time curve (AUC) of daclatsavir, sofosbuvir and GS-331007 was observed between patients with an eGFR below or ≥ 60mL/min. For GS-331007, no relevant changes of trough levels were observed over time. Mean GS-331007 trough levels were 339.5±174.9 ng/mL in patients with an eGFR ≥ 60mL/min and 404.3±226 ng/mL in patients with an eGFR < 60mL/min at day 7 (p=0.52). At day 84, GS-331007 trough levels were 357.8±200.8 ng/mL and 404.2±70.2 ng/mL in patients with an eGFR ≥ 60 mL/min and in patients with an eGFR < 60 mL/min, respectively (p=0.51). The accumulation ratios of renally eliminated GS-331007 for AUC and Cmax did not significantly differ between the two eGFR groups at day 7. An impaired eGFR (30-60 mL/min) does not lead to a dose accumulation of daclatasvir, sofosbuvir and GS-331007. This study provides the rationale for future studies investigating the pharmacokinetic profile of sofosbuvir based HCV treatment in kidney transplant recipients with an eGFR < 30 mL/min.
Fluorescence techniques are known for their high sensitivity and are widely used as analytical tools and detection methods for product and process control, material sciences, environmental and bio-technical analysis, molecular genetics, cell biology, medical diagnostics, and drug screening. According to DIN/ISO 17025 certified standards are used for fluorescence diagnostics having the drawback of giving relative values for fluorescence intensities only. Therefore reference materials for a quantitative characterization have to be related directly to the materials under investigation. In order to evaluate these figures it is necessary to calculate absolute numbers like absorption/excitation cross sections and quantum yield. This can be done for different types of dopands in different materials like glass, glass ceramics, crystals or nano crystalline material embedded in polymer matrices. Based on the optical spectroscopy data we will discuss options for characteristic doped glasses and glass ceramics with respect to scattering and absorption regime. It has shown recently for YAG:Ce glass ceramics that for a proper determination of the quantum efficiency in these highly scattering media a reference material with similar scattering and fluorescent properties is required. This may be performed using the emission decay measurement diagnostics, where the decay time is below 100 ns. In this paper we present first results of these aspects using well performing LUMOGEN RED organic pigments for a comparison of mainly transparent glass with glass ceramics doped with various amounts of dopands e.g. ions of raw earth elements and transition metals. The LUMOGEN red is embedded in silica and polyurethane matrices. Characterisations on wavelength accuracy and lifetime for different environmental conditions (temperature, UV irradiation) have been performed. Moreover intensity patterns and results for homogeneity, isotropy, photo and thermal stability will be discussed. In a next step we will show the transfer of the characterisation methods to inorganic fluophores (YAG:Ce) in silicon. Fluorescence (steady state, decay time) and absorption (remission, absorption) spectroscopy working in different temperature regimes (10 - 350 K) are employed diagnostic methods in order to get a microscopic view of the relevant physical processes and to prove the correctness of the obtained data. The work is funded by BMBF under project number 13N8849.
El desarrollo de receptores sintéticos complejos basados en conceptos de la química supramolecular no garantiza en ocasiones un reconocimiento molecular selectivo. Una alternativa en ciertos aspectos más simple y prometedora es el empleo de materiales híbridos orgánico-inorgánicos preparados mediante la funcionalización de sólidos inorgánicos porosos con receptores sintéticos adecuados. El anclaje de estos sistemas coordinantes a un soporte sólido da lugar a ciertos efectos sinérgicos que no están presentes ni en el material inicial ni en el receptor por separado y que sugieren que estos nuevos materiales híbridos pueden ser empleados en el desarrollo de nuevos sensores y nuevos protocolos de reconocimiento molecular y/o iónico.
The development of synthetic receptors based in supramolecular chemistry concepts will no allow a selective molecular recognition. A more simple, convenient and innovative approach relies on the use of organic-inorganic hybrid materials. These hybrid materials will be prepared by the grafting of certain synthetic receptors onto porous inorganic solids. The grafting of these coordinating systems onto a solid support leads to synergic effects that are hardly achievable with only the synthetic receptors or the solids alone. The presence of these synergic effects suggests that these organic-inorganic hybrid materials will be used for the development of novel sensory systems and novel molecular and/or ionic recognitionprotocols.
Die Entwicklung von Hybridmaterialien mit stark verbesserten Funktionen gelingt durch die Kombination geeigneter Nanomaterialien als Träger mit Motiven aus der supramolekularen Chemie. Diese hetero-supramolekularen Konzepte bieten vielfältige Möglichkeiten, die Lücken zwischen der Molekülchemie, Materialwissenschaften und Nanotechnologie zu schließen. Im Hinblick auf funktionelle Aspekte wurden in jüngster Zeit wichtige Fortschritte erzielt, z. B. verbesserte Erkennungs- und Sensoreigenschaften durch die Anordnung von Molekülen auf vororganisierten Oberflächen, der reversible Aufbau von nanometergroßen Netzwerken und dreidimensionalen Strukturen oder biomimetische und gesteuerte chemische Prozesse in Hybrid-Nanomaterialien, die als Grundlage für hoch spezialisierte Protokolle in dreidimensionalen Gerüststrukturen dienen können. Diese Ansätze ermöglichen eine Feinabstimmung der Eigenschaften von Nanomaterialien und eröffnen neue Perspektiven für die Anwendung supramolekularer Konzepte.
The combination of nanomaterials as solid supports and supramolecular concepts has led to the development of hybrid materials with improved functionalities. These hetero-supramolecular ideas provide a means of bridging the gap between molecular chemistry, materials sciences, and nanotechnology. In recent years, relevant examples have been reported on functional aspects, such as enhanced recognition and sensing by using molecules on preorganized surfaces, the reversible building of nanometer-sized networks and 3D architectures, as well as biomimetic and gated chemistry in hybrid nanomaterials for the development of advanced functional protocols in three-dimensional frameworks. This approach allows the fine-tuning of the properties of nanomaterials and offers new perspectives for the application of supramolecular concepts.
In the second part of this two-part series on the state-of-the-art comparability of corrected emission spectra, we have extended this assessment to the broader community of fluorescence spectroscopists by involving 12 field laboratories that were randomly selected on the basis of their fluorescence measuring equipment. These laboratories performed a reference material (RM)-based fluorometer calibration with commercially available spectral fluorescence standards following a standard operating procedure that involved routine measurement conditions and the data evaluation software LINKCORR developed and provided by the Federal Institute for Materials Research and Testing (BAM). This instrument-specific emission correction curve was subsequently used for the determination of the corrected emission spectra of three test dyes, X, QS, and Y, revealing an average accuracy of 6.8% for the corrected emission spectra. This compares well with the relative standard uncertainties of 4.2% for physical standard-based spectral corrections demonstrated in the first part of this study (previous paper in this issue) involving an international group of four expert laboratories. The excellent comparability of the measurements of the field laboratories also demonstrates the effectiveness of RM-based correction procedures.
Depth profiles of layer systems consisting of different film materials and having different thicknesses are of great practical importance. Multilayer reference coatings of conducting (Ti/Al) and non-conducting (SiO2/Si3N4) material are analyzed with Auger electron spectroscopy (AES) and glow discharge optical emission spectroscopy (GDOES) depth profiling. Deposition techniques, physical vapor deposition for Ti/Al layers and plasma-enhanced chemical vapor deposition for SiO2/Si3N4 layers, as well as measurement and testing procedures for the determination of layer thickness such as optical and mechanical stylus and spectroscopie ellipsometry are discussed. GDOES depth profiles in direct current (d.c.) and radio frequency (r.f.) mode are related to measurements of crater profiles and compared with line scans and depth profiles performed by AES. It is shown that such multilayer reference systems are appropriate for calibration of depth profiles, i.e. the definition and the evaluation of the depth resolution at the interface, the determination of sputter rates both for d.c.- and r.f.-GDOES and AES, the optimization of the conditions of analysis, and the quantification of analysis itself.
The development of fluorescence applications in the life and material sciences has proceeded largely without sufficient concern for the measurement uncertainties related to the characterization of fluorescence instruments. In this first part of a two-part series on the state-of-the-art comparability of corrected emission spectra, four National Metrology Institutes active in high-precision steady-state fluorometry performed a first comparison of fluorescence measurement capabilities by evaluating physical transfer standard (PTS)-based and reference material (RM)-based calibration methods. To identify achievable comparability and sources of error in instrument calibration, the emission spectra of three test dyes in the wavelength region from 300 to 770 nm were corrected and compared using both calibration methods. The results, obtained for typical spectrofluorometric (0°/90° transmitting) and colorimetric (45°/0° front-face) measurement geometries, demonstrated a comparability of corrected emission spectra within a relative standard uncertainty of 4.2% for PTS- and 2.4% for RM-based spectral correction when measurements and calibrations were performed under identical conditions. Moreover, the emission spectra of RMs F001 to F005, certified by BAM, Federal Institute for Materials Research and Testing, were confirmed. These RMs were subsequently used for the assessment of the comparability of RM-based corrected emission spectra of field laboratories using common commercial spectrofluorometers and routine measurement conditions in part 2 of this series (subsequent paper in this issue).
Aggregation-induced emission (AIE) has been meanwhile observed for many dye classes and particularly for fluorophores containing propeller-like groups. Herein, we report on the AIE characteristics of a series of four hydrophobic pyrrolidinylvinylquinoxaline (PVQ) derivatives with phenyl, pyrrolyl, indolyl, and methoxythienyl substituents used to systematically vary the torsion angle between this substituent at the quinoxaline C2 position and the planar PVQ moiety. These molecules, which are accessible via four- or five-component one-pot syntheses, were spectroscopically studied in organic solvents and solvent−water mixtures, as dye aggregates, solids, and entrapped in polystyrene particles (PSP). Steady-state and time-resolved fluorescence measurements revealed a strong fluorescence enhancement for all dyes in ethanol−water mixtures of high water content, accompanying the formation of dye aggregates with sizes of a few hundred nm, overcoming polarity and H-bonding-induced fluorescence quenching of the chargetransfer-type emission of these PVQ dyes. The size and shape of these dye aggregates and the size of the AIE effect are controlled by the water content and the substituent-dependent torsion angle that influences the nucleation process and the packing of the molecules during aggregation. Staining of 1 μm-sized carboxy-functionalized PSP with the PVQ dyes resulted also in a considerable increase in the fluorescence quantum yield and lifetime, reflecting the combined influence of the restricted molecular motion and the reduced polarity of the dye microenvironment.
Multiple anthropogenic stressors cause worldwide amphibian declines. Among several poorly investigated causes is global pollution of aquatic ecosystems with endocrine disrupting compounds (EDCs). These substances interfere with the endocrine system and can affect the sexual development of vertebrates including amphibians. We test the susceptibility to an environmentally relevant contraceptive, the artificial estrogen 17α-ethinylestradiol (EE2), simultaneously in three deeply divergent systematic anuran families, a model-species, Xenopus laevis (Pipidae), and two non-models, Hyla arborea (Hylidae) and Bufo viridis (Bufonidae). Our new approach combines synchronized tadpole exposure to three EE2-concentrations (50, 500, 5,000 ng/L) in a flow-through-system and pioneers genetic and histological sexing of metamorphs in non-model anurans for EDC-studies. This novel methodology reveals striking quantitative differences in genetic-male-to-phenotypic-female sex reversal in non-model vs. model species. Our findings qualify molecular sexing in EDC-analyses as requirement to identify sex reversals and state-of-the-art approaches as mandatory to detect speciesspecific vulnerabilities to EDCs in amphibians.
Amphibians are undergoing a global decline. One poorly investigated reason could be the pollution of aquatic habitats by endocrine disrupting compounds (EDCs). We tested the susceptibility to the synthetically stabilized estrogen 17α-ethinylestradiol (EE2) in three deeply diverged anuran species, differing in sex determination systems, types of gonadogenesis and larval ecologies. To understand whether data from the amphibian model Xenopus laevis (Pipidae) are analogous and applicable to only distantly related non-model amphibians, tadpoles of X. laevis, Hyla arborea (Hylidae) and Bufo viridis (Bufonidae) were simultaneously exposed to 50, 500 and 5000 ng/L EE2 from hatching until completion of metamorphosis, using a flow-through-system under identical experimental conditions. Comparing molecularly established genetic with histologically assessed phenotypic sex in all species, we have recently shown that EE2 provoked numerous genetic-male-to-phenotypic-female sex reversals and mixed sex individuals, confirming overall its expected feminizing effect. In the present study, we focus on the influence of EE2 on gonadal and somatic development. Anatomy and histology revealed several species-specific effects. In both non-model species, H. arborea and B. viridis, high numbers of anatomically impaired gonads were observed. In H. arborea, exposed to 5000 ng/L EE2, numerous underdeveloped gonads were detected. Whereas EE2 did not alter snout-to-vent length and body weight of X. laevis metamorphs, H. arborea showed a treatment-dependent decrease, while B. viridis exhibited an increase in body weight and snout-to-vent length. Apart from a concentration-dependent occurrence of yellowish skin color in several H. arborea, no organ-specific effects were detected. Since EE2 ubiquitously occurs in many aquatic ecosystems and affects sexual and somatic development, among EDCs, it may indeed contribute to amphibian decline. The inter-species variation in developmental EE2-effects corroborates species-specific vulnerability differences towards EDCs between deeply diverged amphibian groups
Ananion-dopedaluminiumchlorofluoride AlCl0.1F2.8(OTeF5)0.1(ACF-teflate) was synthesized.The material contains pentafluor-oorthotellurate(teflate)groups, which mimic fluoride ions electronically, but are sterically more demanding. They are embedded into the amorphous structure. The latter was studied by PDF analysis, EXAFS data and MAS NMR spectroscopy. The mesoporous powder is a Lewis superacid, and ATR-IR spectra of adsorbed CD3CN reveal a blue-shift of the adsorption band by73 cm-1, which is larger than the shift for SbF5. Remarkably,ACF-teflate catalyzes dehydrofluorination reactions of mono-fluoroalkanes to yield olefins in C6D6. In these cases,no Friedel-Crafts products were formed.